1. Field of the Invention
The field of the invention is bio-affecting and body treating compositions of iopamidol, protamine, and ethiodized oil.
2. Description of Related Art
Hepatocellular carcinoma (HCC) has become increasingly prevalent in the United States (Altekruse S F et al., J Clin Oncol 2009, 27, 1485-91; El-Serag H B et al., Arch Intern Med 2007, 167, 1983-9). Systemic treatments for HCC have limited efficacy and inherent toxicity (Worns M A et al., Dig Dis 2009, 27, 175-88). In contrast, the use of chemoembolization (Brown D B et al., J Vasc Intery Radiol 2009, 20, S425-34) to treat HCC allows for localized, concentrated delivery of chemotherapeutic agents resulting in less systemic toxicity, improved quality of life, and significant prolongation of survival (Lau W Y, Lai E C, Hepatobiliary Pancreat Dis Int 2008, 7, 237-57). However, the benefits of chemoembolization may be less dramatic in patients with advanced disease (large, multifocal, and/or infiltrative tumor, vascular invasion, severe cirrhosis) (Kothary N et al., J Vasc Intery Radiol 2007, 18, 1517-26) and new treatment strategies are being actively pursued.
Over decades of trial and error, chemoembolization has been iteratively improved for localized delivery to the tumor site incorporating cytotoxic chemotherapeutic agents, a lipid component to enhance tumor uptake, a contrast agent for fluoroscopic visualization, and embolic material to impede washout and induce ischemia. The chemoembolization strategy is suited to treat HCC given the arterial blood supply to tumors and the inherent avidity of HCC for ethiodized oil (Bruix J et al., Gastroenterology 2004, 127, S179-88, Maleux G et al., Dig Dis 2009, 27, 157-63). In vitro studies, including electron microscopy analysis, have shown that emulsified ethiodized oil droplets are taken up by hepatoma cells via endocytosis, a process that is more active in these cells than in hepatocytes (Chou F I et al., Nucl Med Biol 1995, 22, 379-86). The viscosity of the ethiodized oil emulsion also allows it to act as an embolic agent, reducing blood flow to the tumor and decreasing washout of the chemotherapeutic agents. This increases the intratumoral area under curve (AUC) while decreasing the systemic exposure to the chemotherapeutic agents (Lau W Y, Lai E C, Hepatobiliary Pancreat Dis Int 2008, 7, 237-57).
In addition to chemoembolization, researchers have explored the use of gene therapy as an HCC treatment strategy. Delivery of thymidine kinase, tumor suppressor genes, and anti-angiogenesis genes into tumor cells would afford improved drug selectivity and possibly tumor growth attenuation (Mohr L et al., Expert Opin Biol Ther 2002, 2, 163-75; Peñuelas I et al., Gastroenterology 2005, 128, 1787-95). Although there are a number of genes with oncocidal activity, the difficult problem of achieving efficient gene delivery while maintaining acceptable indices of toxicity remains a challenge. Both viral and nonviral gene delivery vectors have been developed with viral vectors being more efficient gene carries (Boeckle S, Wagner E, AAPS J 2006, 8, E731-42). Unfortunately, the host's immune response limits both the safety and efficacy of viral vectors (Boeckle S, Wagner E, AAPS J 2006, 8, E731-42; Descamps D, Benihoud K, Curr Gene Ther 2009, 9, 115-27; Massari I et al., Exp Gerontol 2002, 37, 823-31). In the context of HCC, animal studies have shown the utility of combining chemoembolization and trans-arterial nonviral gene therapy strategies. Kim et al. demonstrated that an emulsion of ethiodized oil, an aqueous contrast agent, and condensed polyethyleneimine:DNA particles could deliver plasmid DNA to VX2 liver tumors in a rabbit model (Kim Y I et al., Radiology 2006, 240, 771-7). Although gene transfection was significant, polyethyleneimine has a prohibitive toxicity profile, making clinical translation difficult (Hunter A C, Adv Drug Deliv Rev 2006, 58, 1523-31).